PROJECT SUMMARY Antibody therapy becomes indispensable for the treatment of infection, cancer, and inflammatory disease. Nevertheless, clinical responses to antibody therapy vary markedly and efficacies of antibody therapy are largely unpredictable in patients. To date, the genetic factors affecting the efficacy of antibody therapy remain incompletely understood. Almost all successful therapeutic antibodies are IgGs, which require IgG Fc receptors (or Fc?Rs) on immune cells to elicit effective immune functions. Fc?Rs are essential links between target cells opsonized by therapeutic antibodies and effector immune cells that are responsible for killing the infected and abnormal cells in immunotherapy. Humans use a number of Fc?Rs to mediate distinctive immune cellular functions and functional Fc?R genetic variants significantly impact immune responses. In preliminary studies, we found that human CD177 specifically binds IgG but to IgA, suggesting that CD177 is an IgG Fc receptor. CD177 is selectively expressed in bone marrow cells and has a role in the proliferation and differentiation of myeloid lineage cells including neutrophils, myelocytes, promyelocytes, megakaryocytes, and early erythroblasts. CD177 is exclusive expressed on neutrophils among circulating leukocytes with the percentages of CD177+ neutrophils ranging from 0% to 100% in individuals. Notably, CD177 deficiency is a common phenotype as 3?5% human populations completely lack CD177 expression. Our group was the first to delineate genetic mechanisms of CD177 deficiency and expression variations. CD177 is able to mediate neutrophil activation, but the physiological ligands and immune functions of CD177 remain poorly understood. We hypothesize that CD177 is a novel IgG Fc receptor and that the CD177 genetic variants significantly affect IgG-mediated immune functions. The rationale/premise of the proposed study is that the definition of CD177 as novel functional IgG Fc-receptor will fill the critical knowledge gap about the full repertoire of human Fc?Rs, which are essential for antibody-mediated responses. We will test our hypothesis by pursuing the following Specific Aims: 1) to test the hypothesis that CD177 is a novel IgG Fc receptor (Fc?R); 2) to test the hypothesis that CD177 genetic variants affect the interaction between human IgG and CD177; and 3) to test the hypothesis that CD177 affects IgG-mediated immune functions. Our study will provide novel insights into CD177-mediated immune functions and into the genetic mechanisms underlying response variability of antibody therapy. CD177 may serve as valuable biomarkers in antibody therapy and vaccinations.